Gene-chemical interactions in the developing mammalian nervous system: Effects on proliferation, neurogenesis and differentiation

Abstract

The orderly formation of the nervous system requires a multitude of complex, integrated and simultaneously occurring processes. Neural progenitor cells expand through proliferation, commit to different cell fates, exit the cell cycle, generate different neuronal and glial cell types, and new neurons migrate to specified areas and establish synaptic connections. Gestational and perinatal exposure to environmental toxicants, pharmacological agents and drugs of abuse produce immediate, persistent or late-onset alterations in behavioral, cognitive, sensory and/or motor functions. These alterations reflect the disruption of the underlying processes of CNS formation and development. To determine the neurotoxic mechanisms that underlie these deficits it is necessary to analyze and dissect the complex molecular processes that occur during the proliferation, neurogenesis and differentiation of cells. This symposium will provide a framework for understanding the orchestrated events of neurogenesis, the coordination of proliferation and cell fate specification by selected genes, and the effects of well-known neurotoxicants on neurogenesis in the retina, hippocampus and cerebellum. These three tissues share common developmental profiles, mediate diverse neuronal activities and function, and thus provide important substrates for analysis. This paper summarizes four invited talks that were presented at the 12th International Neurotoxicology Association meeting held in Jerusalem, Israel during the summer of 2009. Donald A. Fox described the structural and functional alterations following low-level gestational lead exposure in children and rodents that produced a supernormal electroretinogram and selective increases in neurogenesis and cell proliferation of late-born retinal neurons (rod photoreceptors and bipolar cells), but not Müller glia cells, in mice. Lisa Opanashuk discussed how dioxin [TCDD] binding to the arylhydrocarbon receptor [AhR], a transcription factor that regulates xenobiotic metabolizing enzymes and growth factors, increased granule cell formation and apoptosis in the developing mouse cerebellum. Alex Zharkovsky described how postnatal early postnatal lead exposure decreased cell proliferation, neurogenesis and gene expression in the dentate gyrus of the adult hippocampus and its resultant behavioral effects. Bernard Weiss illustrated how environmental endocrine disruptors produced age- and sex-dependent alterations in synaptogenesis and cognitive behavior.

Figure 1. Histological staining of adult control and gestationally lead-exposed rat with the nuclear stain DAPI

Relative to controls, the thickness of the outer (ONL) and inner (INL) nuclear layer increased in the low-level and moderate-level gestationally lead-exposed rats. Scale bar equals 20 μm.

Figure 2. Genes associated with the regulation of GNP proliferation are increased following TCDD Exposure

Mice were exposed to vehicle (DMSO) or TCDD (1.0 μg/kg) by oral gavage on postnatal day 6 and cerebella were removed 8 hours later. RNA was isolated and gene expression was analyzed by RT-PCR. Gene expression was normalized to GAPDH. Values represent mean ± SEM (n = 4) and were analyzed using a Student’s t-test. p< 0.05 relative to vehicle control.

Figure 3. Production of the new cells in the rat dentate gyrus, following postnatal lead exposure

Light microscopic images of the BrdU-labeled cells in (A) control and (B) lead-exposed rats. The (C) number of BrdU-positive cells and (D) volume of dentate gyrus in control and lead-exposed rats. Values represent mean ± SEM (n = 6) and were analyzed using a Student’s t-test. p< 0.05 relative to vehicle control.